Ruthenium-catalyzed C – H / O – H and C – H / N – H bond functionalizations : oxidative annulations of cyclopropyl-substituted alkynes †

The chemical behavior of cyclopropyl-substituted alkynes has been probed using the reaction conditions of ruthenium-catalyzed oxidative C–H/O–H and C–H/N–H bond functionalizations. The oxidative annulations proceeded with complete conservation of all cyclopropane fragments and allowed for the one-step preparation of synthetically useful cyclopropyl-substituted isocoumarins and isoquinolones with high regioselectivities and chemical yields. The connectivities of the key heterocyclic products were unambiguously established by X-ray diffraction analysis.


Introduction
Transition metal-catalyzed reactions have matured to being among the most powerful tools in organic chemistry. 1Particularly, direct functionalizations 2 of aromatic C-H bonds have received considerable recent attention as ecologically and economically friendly synthetic methods, that avoid the use of prefunctionalized starting materials.Yet, an even more sustainable strategy is represented by the simultaneous transition metal-catalyzed C-H/O-H or C-H/N-H bond functionalizations utilizing arenes or alkenes 1 (Scheme 1).
This approach allowed for the one-pot preparation of synthetically useful heterocycles 3, such as substituted isoquinolinones, isoquinolones, isocoumarins, α-pyrones and 2-pyridones, many of which possess valuable biological activities 3a-e and represent key structural scaffolds of naturally occurring compounds.3f-l Consequently, a number of valuable protocols for intermolecular oxidative annulations with alkynes 2 have been developed, 4,5 with ruthenium-catalyzed 4 cyclizations being among the most promising.
The attachment of a cyclopropyl fragment to heterocyclic molecules frequently modifies their pharmacological properties and significantly enhances their biological activities. 6For instance, a number of well-known antibacterial agents, such as Ciprofloxacin, Sparfloxacin, Grepafloxacin and WIN-57294, contain a 1-cyclopropylquinolin-4(1H)-one moiety.6e,f However, the inherently high molecular strain in cyclopropanes (28.1 kcal mol −1 ) 7 is reflected by some specificity to the chemistry of cyclopropane-containing molecules.As a consequence, metal-mediated or -catalyzed reactions with participation of (cyclopropylcarbinyl) metal intermediates proceeded almost exclusively via opening of at least one cyclopropane ring, 8 whereas formation of cyclopropane-containing compounds was observed as a side reaction only.Given the remarkable biological activity of cyclopropyl-decorated heterocycles along with the challenges associated with the use of cyclopropyl-substituted alkynes 2 in transition-metal catalysis, we, thus, became attracted to exploring their unprecedented oxidative annulations by metal-catalyzed C-H/Het-H bond functionalization with rather inexpensive ruthenium catalysts, on which we wish to report herein.

Results and discussion
To elucidate the synthetic versatility of the transformation as well as the influence and reactivity of cyclopropyl substituents in the alkynes 2, we set out to perform detailed synthetic and structural studies on atom-and step-economical rutheniumcatalyzed C-H/O-H and C-H/N-H bond functionalizations of representative benzoic acids 4a-d and benzamides 5a-i with various cyclopropylacetylenes 2 (Fig. 1).
We initiated our studies by exploring the reactivity of substituted benzoic acids 4 and cyclopropylarylethynes 2 in ruthenium-catalyzed oxidative annulations 4f (Scheme 2).Notably, arylalkynes displaying a cyclopropyl substituent yielded the desired product through the C-H/O-H bond functionalizations reaction manifold.Thus, the highest yield was observed for the alkyne 2a in the reaction with the acid 4c, while the yield decreased with alkyne 2e possessing an electron-withdrawing substituent.However, the influence of the substituents in benzoic acids 4 was found to be less pronounced.
No product formation was observed in the reactions of substrate 4a with alkyne 2d and when using starting materials 4d and 2a, while the corresponding isocoumarin 6dk was formed in the reaction of 4d with diethylethyne in 31% yield.† The influence of the cyclopropyl moieties upon the course of chemical transformations by the stabilization of key reaction intermediates due to conjugation is well documented. 9owever, several representative experiments with p-anisic acid (4b) and selected alkynes 2 (Table 1) indicated the cyclopropyl substituents in the alkynes 2 to translate into a reduction of their reactivity (entry 1), but demonstrated no significant influence onto the regioselectivity of the annulation.Indeed, the reaction with ( pent-1-ynyl)cyclopropane (2h) furnished a 1 : 1 mixture of the two regioisomeric isocoumarins 6bh and 7bh (entry 2), thereby indicating a negligible effect of steric interactions 10 in these annulations.Furthermore, the electronic effect of the cyclopropane appeared to be of less importance for the overall regioselectivity.
It is noteworthy that the rhodium-catalyzed annulation of unsymmetrically substituted arylalkyl alkynes Alk-CuC-Ar delivered mixtures of 3-and 4-arylsubstituted regioisomeric products 11,12 in ratios of 6 : 1 to 8 : 1. 5i,j In spite of the previously reported almost exclusive formation of 3-arylsubstituted products, 4e the cyclization of alkyne 2i afforded in our hands heterocycles 7bi and 6bi in a ratio of 9.4 : 1 (Table 1, entry 3).
In the ruthenium-catalyzed cyclizations of unsymmetrical cyclopropylacetylenes the ratios of regioisomeric products 6 and 7 varied from 1 : 1 to 13 : 1 (Scheme 2 and Table 1).To   elaborate spectroscopic criteria † for this group of cyclopropylsubstituted heterocycles, the structures of cyclopropylisocoumarins 6aa, 6ae and 7aa have been unambiguously established by X-ray diffraction analysis (Fig. 2).Notably, both 3-aryl-4cyclopropyl-substituted heterocycles 6aa and 6ae adopted essentially the same conformations with the dihedral angles C1-C2-C3-center (C4-C5) being equal to −99.5°and −96.8°, respectively, while the dihedral angles between heterocyclic and carbocyclic aromatic moieties were found to be 47.3 and 37.6°, respectively.In contrast, in 7aa the dihedral angle C1-C2-C3-centre (C4-C5) = 179.4°with the angle between aromatic planes of 66.5°, i.e. with almost ideal conditions for the conjugation of cyclopropyl and isocoumarin fragments.† Somewhat similar tendencies were observed in rutheniumcatalyzed C-H/N-H bond functionalizations in benzamides 5 with (cyclopropylethynyl)benzenes 2, the results of which are summarized in Scheme 3. Generally, the oxidative annulations occurred with high yields and synthetically useful regioselectivity.While the catalytic system displayed a high functional group tolerance, the attempted cyclization of amide 5a with cyclopropylnaphthylalkyne 2d gave less satisfactory results.† Furthermore, cyclopropylaryl alkynes 2c and 2e possessing electron-withdrawing substituents on the aromatic rings delivered the corresponding products 8ac and 8ae, respectively, in somewhat lower yield.However, a number of oxidative cyclizations, including the reaction of the parent compounds 2a and 5a, proceeded in a regiospecific manner affording only regioisomers 8 (8aa, 8ac, 8ae, 8af and 8ca), while in the other cases the ratio of heterocycles 8 and 9 varied from 9.8 (8ia) to 3.6  (8ab).Surprisingly, the best yield (83%) was obtained when utilizing dicyclopropylacetylene (2g), which was less reactive in the ruthenium-catalyzed isocoumarin synthesis (vide supra).Unfortunately, the attempted synthesis of N-cyclopropyl-3(4)cyclopropylisoquinolones 8ea and 9ea occurred less efficiently.Moreover, the benzamide 5e did not react with diphenylacetylene (tolane) under otherwise identical reaction conditions.
It is particularly noteworthy that all the ruthenium-catalyzed oxidative C-H/Het-H bond functionalizations proceeded with complete conservation of all cyclopropane fragments. 8,14s a consequence, cyclopropylethynes can be utilized in ruthenium-catalyzed C-H/Het-H bond functionalizations for the preparation of valuable cyclopropyl-substituted heterocycles.According to the mechanistic rationalizations generally accepted for ruthenium-catalyzed C-H/Het-H bond functionalization with alkynes, 4a,b,d-g the regiochemistry-determining step of these oxidative reactions is constituted by the insertion of alkyne 2 into the ruthenium-carbon bond of key intermediate 10 to give the seven-membered ruthenacycle 11 (Scheme 4).Thus, the observed regioselectivities can for instance be rationalized by the enhanced thermodynamic stability of regioisomer 11, in which the aryl substituent is in the neighboring position to the ruthenium.

Experimental
Scheme 4 Regiochemistry-determining step of the ruthenium-catalyzed C-H/ Het-H and C-H/N-H bond functionalizations.

Fig. 3
Fig.3Molecular structures of isoquinolones 8aa and 8ah in the crystal13   (numbering does not correspond to the IUPAC rules).